Menopause is associated with physical frailty and limitations in musculoskeletal function. Tendons, which connect skeletal muscle to bone, are essential for musculoskeletal function. The prevalence of tendon injuries is much higher in postmenopausal women when compared to premenopausal women. The functional integrity of tendon connective tissue is dependent on its collagen-rich extracellular matrix (ECM), but recent data suggest that estrogen-deficiency results in a large decline in tendon collagen. Estrogen deficiency is also associated with a decrease in tendon collagen turnover and increased activity of ECM-degrading matrix metalloproteinases (MMPs). Current approaches for reducing the negative effects of menopause include estrogen therapy (ET) but ET leads to reduction in tendon fibril diameter and stiffness in postmenopausal women. In contrast, genistein, a phytoestrogen in the category of isoflavones, has been shown to maintain tendon collagen in estrogen-deficient rats. Our understanding of how novel therapies, such as genistein, affect connective tissue structures is severely limited. It is not known if genistein treatment produces favorable effects on tendon mechanical properties in estrogen-deficient rats. Moreover, the cellular mechanisms contributing to the effect of genistein on tendon collagen have also remained unexplored. The objective of this application is to determine, in vivo, if genistein improves tendon function and structure in a rat model of estrogen-deficiency and to identify novel mechanisms that mediate the effect of genistein on tendon remodeling. The rationale for this work is to improve our understanding of the mechanisms and potential therapeutic benefits of genistein on connective tissues. With the growing elderly population it is essential that we continue to explore novel therapeutic interventions for postmenopausal problems, especially those that benefit connective tissues. This proposal combines functional and mechanistic studies to evaluate the positive health benefits of genistein on connective tissue, a largely overlooked aspect of menopause. This lack of knowledge represents a critical barrier to the development of effective therapies, which will reduce the negative impact of estrogen deficiency on tendon health in postmenopausal women. We expect our findings will reduce this knowledge gap and, combined with future investigations, provide evidence that genistein could be used to maintain collagenous tissues in cases of estrogen-deficiency.